TY - JOUR
T1 - Comparative assessment of antitumor effects and autophagy induction as a resistance mechanism by cytotoxics and EZH2 inhibition in INI1-negative epithelioid sarcoma patient-derived xenograft
AU - Stacchiotti, Silvia
AU - Zuco, Valentina
AU - Tortoreto, Monica
AU - Cominetti, Denis
AU - Frezza, Anna Maria
AU - Percio, Stefano
AU - Indio, Valentina
AU - Barisella, Marta
AU - Monti, Valentina
AU - Brich, Silvia
AU - Astolfi, Annalisa
AU - Colombo, Chiara
AU - Pasquali, Sandro
AU - Folini, Marco
AU - Gounder, Mrinal M.
AU - Pantaleo, Maria A.
AU - Collini, Paola
AU - Tos, Angelo Paolo Dei
AU - Casali, Paolo Giovanni
AU - Gronchi, Alessandro
AU - Zaffaroni, Nadia
PY - 2019/7
Y1 - 2019/7
N2 - Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline-and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90%) was caused by gemcitabine, EPZ-011989, and the doxorubicin–ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin–ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.
AB - Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline-and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90%) was caused by gemcitabine, EPZ-011989, and the doxorubicin–ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin–ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.
KW - Autophagy
KW - Epithelioid sarcoma
KW - EZH2
KW - HMGA2
KW - PDX
UR - http://www.scopus.com/inward/record.url?scp=85071195471&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071195471&partnerID=8YFLogxK
U2 - 10.3390/cancers11071015
DO - 10.3390/cancers11071015
M3 - Article
AN - SCOPUS:85071195471
VL - 11
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 7
M1 - 1015
ER -